Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this review, El Moghrabi et al. provide an updated overview of the current knowledge on the role of cannabinoids in cancer therapy. The authors first outline the different mechanisms of cell death, which is an appropriate and clarifying section. They then compile the available evidence regarding the most extensively studied phytocannabinoids — THC, CBD, CBN, CBG, and CBC — and this section is well selected and well discussed. They subsequently focus on two synthetic cannabinoids, reporting the main mechanisms by which these compounds induce cancer cell death across diverse tumor types, in both in vitro and in vivo models. However, the rationale for selecting these particular synthetic cannabinoids is unclear and should be revised, as detailed below.

Table 1 provides a useful compilation of the mechanisms by which the different cannabinoids trigger cell death in various cancer models, and Section 4 offers a clear overview of the current state of clinical trials and approved cannabinoid-based drugs, together with their indications, giving readers a good sense of the current landscape and its potential future evolution. The cited references are also appropriate and up to date.

In summary, this is a solid review that summarizes current knowledge on the mechanisms underlying the antitumor effects of cannabinoids. However, some aspects require revision to improve its clarity and usefulness for readers in the field. These are detailed below.

Major comments

1. The rationale for selecting the two synthetic cannabinoids discussed is not clearly justified. Several other synthetic cannabinoids exist such as metabolically stable analogues of endocannabinoids, or derivatives such as HU-210 or HU-308. The authors should clarify their selection criteria and consider including additional compounds to provide a more comprehensive and in-depth review.
2. A schematic figure illustrating the molecular pathways and mechanisms involved in the antitumor effects of cannabinoids would substantially improve the manuscript. Such a figure would help readers visualize the different pathways, their interrelationships, and which pathways are activated or inhibited by each cannabinoid.

Minor comments

1. Figure 1A: The chemical structures and accompanying text should be enlarged, as they are difficult to read at the current size. Additionally, in the structure of THC, the hydroxyl group should be represented as "OH" rather than "O-H."
2. Figure 1B: The legend should specify the time period over which the analyzed articles were published/searched.
3. Line 67: The phrase "among these endocannabinoids" should be removed, as it does not fit grammatically or logically within the sentence.
4. Line 523: The phrase "known as liquid or herbal incense" should be deleted.

Author Response

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Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

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Comments for author File: Comments.pdf

Author Response

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Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed my main concerns and I consider that the manuscript is now suitable for publication.

Author Response

We thank the reviewer for their expertise and constructive comments that enhanced the content and scope of our review.

Reviewer 2 Report

Comments and Suggestions for Authors

I think the scientific c revisions made are good, particularly the stronger caution stated about the mechanistic casualty, tumor-model heterogeneity, and more importantly the limitation of preclinical evidence, and the need for functional validation. A final human proof-reading pass is essential.

Comments for author File: Comments.pdf

Comments on the Quality of English Language

English is fine. 

Author Response

Please see the attachment.

Author Response File: Author Response.docx